Chromogranina A i jej rola w patogenezie cukrzycy

Chromogranin A is a member of the granin glycoprotein family that is expressed by the endocrine and neuroendocrine cells of different organs. Intracellularly, chromogranin A contributes to the regulation of secretion and gives several cleavage products after secretion. Some of its cleavage products modify the hormone functions in autocrine and paracrine ways, while the functions of others have not been fully understood yet. Serum chromogranin A level is most prominently used in neuroendocrine tumour diagnostics. In addition, recent studies have suggested that chromogranin A and some of its cleavage products (pancreastatin and WE-14) also play important roles in the pathogenesis of the various forms of diabetes mellitus, but their exact mechanisms still need to be clarified. Higher chromogranin A, pancreastatin, and WE-14 levels have been reported in type 1, type 2, and gestational diabetic patients compared to healthy controls. A notable connection has been inferred through the observation that type 1 diabetes mellitus is not at all or rarely developed in chromogranin A gene-knockout, non-obese diabetic model mice compared to non-knockout, non-obese diabetic mice. Pancreastatin inhibits insulin release in various cell and animal models, and WE-14 serves as an autoantigen for both CD4+ and CD8+ beta cell-destructive diabetogenic T-cell clones in type 1 diabetes. Chromogranin A contributes to the pathogenesis of diabetes mellitus according to the available literature. The current findings facilitate further investigation to unravel the deeper relationships between this glycoprotein and diabetes

Investigation of changes in thickness and reflectivity from layered retinal structures of healthy and diabetic eyes with optical coherence tomography

OCT is usually employed for the measurement of retinal thickness. However, coherent reflected light carries more information characterizing the optical properties of tissue. Therefore, optical property changes may provide further information regarding cellular layers and early damage in ocular diseases. We investigated the possibility of OCT in detecting changes in the optical backscattered signal from layered retinal structures. OCT images were obtained from diabetic patients without retinopathy (DM, n = 38 eyes) or mild diabetic retinopathy (MDR, n = 43 eyes) and normal healthy subjects (n = 74 eyes). The thickness and reflectivity of various layered structures were assessed using a custom-built algorithm. In addition, we evaluated the usefulness of quantifying the reflectivity of layered structures in the detection of retinal damage. Generalized estimating equations considering within-subject inter-eye relations were used to test for differences between the groups. A modified p value of <0.001 was considered statistically significant. Receiver operating characteristic (ROC) curves were constructed to describe the ability of each parameter to discriminate between the eyes of DM, MDR and healthy eyes. Thickness values of the GCL + IPL and OPL showed a significant decrease in the MDR eyes compared to controls. Significant decreases of total reflectance average values were observed in all layers in the MDR eyes compared with controls. The highest AUROC values estimated for the total reflectance were observed for the GCL + IPL, OPL and OS when comparing MDR eyes with controls. Total reflectance showed a better discriminating power between the MDR eyes and healthy eyes compared to thickness values. Our results suggest that the optical properties of the intraretinal layers may provide useful information to differentiate pathological from healthy eyes. Further research is warranted to determine how this approach may be used to improve diagnosis of early retinal neurodegeneration

Regular chromogranin A monitoring facilitated the early detection of a gastrointestinal neuroendocrine tumour in a patient with type 1 diabetes

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Association of hypoxia inducible factor-1 alpha gene polymorphism with both type 1 and type 2 diabetes in a Caucasian (Hungarian) sample

BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1alpha) is a transcription factor that plays an important role in neo-vascularisation, embryonic pancreas beta-cell mass development, and beta cell protection. Recently a non synonymous single nucleotide polymorphism (g.C45035T SNP, rs11549465) of HIF-1alpha gene, resulting in the p.P582S amino acid change has been shown to be associated with type 2 diabetes (T2DM) in a Japanese population. Our aim was to replicate these findings on a Caucasian (Hungarian) population, as well as to study whether this genetic effect is restricted to T2DM or can be expanded to diabetes in general. METHODS: A large Caucasian sample (N = 890) was recruited including 370 T2DM, 166 T1DM and 354 healthy subjects. Genotyping was validated by two independent methods: a restriction fragment analysis (RFLP) and a real time PCR using TaqMan probes. An overestimation of heterozygotes by RFLP was observed as a consequence of a nearby SNP (rs34005929). Therefore genotyping results of the justified TaqMan system were accepted. The measured genotype distribution corresponded to Hardy-Weinberg equilibrium (P = 0.740) RESULTS: As the TT genotype was extremely rare in the population (0.6% in clinical sample and 2.5% in controls), the genotypes were grouped as T absent (CC) and T present (CT and TT). Genotype-wise analysis showed a significant increase of T present group in controls (24.0%) as compared to patients (16.8%, P = 0.008). This genetic effect was demonstrated in the separated samples of type 1 (15.1%, P = 0.020), and also in type 2 (17.6%, P = 0.032) diabetes. Allele-wise analysis gave identical results showing a higher frequency of the T allele in the control sample (13.3%) than in the clinical sample (8.7%, P = 0.002) with similar results in type 1 (7.8%, P = 0.010) and type 2 (9.1%, P = 0.011) diabetes. The odds ratio for diabetes (either type 1 or 2) was 1.56 in the presence of the C allele. CONCLUSION: We confirmed the protective effect of a rare genetic variant of HIF-1alpha gene against type 2 diabetes in a Caucasian sample. Moreover we demonstrated a genetic contribution of the same polymorphism in type 1 diabetes as well, supporting a possible overlap in pathomechanism for T2DM and a T1DM

Aminoguanidin-kezeles pozitiv hatasa a peroxinitrit-termelodesre es szivhipertrofiara streptozotocinnal indukalt diabeteses patkanyokban

The effect and possible mechanisms of action of aminoguanidine (a preferential iNOS inhibitor) has been studied on cardiovascular damages and overproduction of reactive nitrogen species in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: 40 rats were divided into five groups (control and diabetic, with or without aminoguanidine treatment, diabetic with insulin treatment) and oxidative stress parameters were examined. Tissue nitric oxide levels were determined by EPR spectroscopy, while peroxynitrite generation by a chemiluminescence method. Cardiac hypertrophy, blood metabolic parameters (blood glucose, HbA1c, fructosamine), as well as tissue protein carbonyl levels were also determined. RESULTS: Diabetic animals showed increased nitric oxide and peroxynitrite generation in the aorta along with a significant hypertrophy and protein carbonylation of the cardiac tissue. Both aminoguanidine and insulin treatment suppressed high levels of nitric oxide and peroxynitrite in the vasculature, but only aminoguanidine was able to prevent hypertrophic alterations and to reduce protein carbonylation in the heart. CONCLUSIONS: The results show that (1) aminoguanidine reduces nitric oxide production and prevents cardiac hypertrophy, (2) insulin therapy improves carbohydrate metabolism, reduces nitrosative stress but has no effect on cardiac hypertrophy. Cardiac hypertrophy in diabetes is strongly correlated with non-enzymatic glycation. Aminoguanidine prevented hypertrophy by blocking the formation of advanced glycation end products rather than via other mechanisms

Beneficial effects of aminoguanidine on the cardiovascular system of diabetic rats

BACKGROUND: The study focused on investigating the effect of aminoguanidine on cardiovascular damages in diabetes and the possible mechanisms of its action. METHODS: Aminoguanidine (AMNG) was used to treat streptozotocin-induced diabetic rats, and the effects were compared to those obtained under insulin treatment. Blood metabolic parameters, *NO and ONOO- as well as protein carbonyl levels and cardiac hypertrophy were determined. RESULTS: Diabetic animals showed increased *NO levels and markedly increased ONOO- generation in the aorta, along with a significant hypertrophy and protein carbonylation in the cardiac tissue. Both AMNG and insulin treatment suppressed the levels of overproduced *NO or ONOO- in the vasculature, but only AMNG was able to prevent hypertrophic alterations and reduce protein carbonylation in the cardiac tissue. CONCLUSIONS: Oxidative protein modification, together with cardiac hypertrophy and high generation of *NO and ONOO-, are important early events in the development of cardiovascular complications in diabetes. Aminoguanidine could prevent hypertrophy through inhibition of production of nonenzymatic glycation products rather than via inhibition of *NO production

Personalized Indicator Thrombocytosis Shows Connection to Staging and Indicates Shorter Survival in Colorectal Cancer Patients with or without Type 2 Diabetes

Background: Pre- and postoperative thrombocytosis was reported to have significant effect on patient survival. However, the definition of thrombocytosis throughout the literature is not unified. Methods: A retrospective longitudinal observational study has been conducted with the inclusion of 150 colorectal cancer (CRC) patients and 100 control subjects. A new measure of platelet changes at an individual level, named personalized indicator thrombocytosis (PIT) was defined, including 4 anemia adjusted variants. Results: In concordance with the literature, PIT values of control subjects showed a slow decrease in platelet counts, while PIT values of CRC patients were significantly higher (p &lt; 0.0001). More advanced staging (p &lt; 0.0001) and both local (p &le; 0.0094) and distant (p &le; 0.0440) metastasis are associated with higher PIT values. Higher PIT values suggested shorter survival times (p &lt; 0.0001). Compared to conventional, a PIT-based definition resulted in approximately 3-times more patients with thrombocytosis. 28% and 77% of the deceased patients had conventional- and PIT-based thrombocytosis, respectively. Conclusions: Compared to conventional thrombocytosis, as an individual metric, PIT values may indicate the condition of patients more precisely. Possible future applications of PIT may include its usage in therapy decision and early cancer detection; therefore, further investigations are recommended

Szabadgyokok es reaktiv nitrogen speciesek szerepe a diabetes kesoi szovodmenyeinek kialakulasaban patkanyban

In this time-course study the levels of different reactive species, especially those of nitric oxide and peroxynitrite were determined in streptozotocin-induced diabetic rat tissues at different time-points after the onset of the disease, before the development of histopathological damages. Significantly higher steady state free radical concentrations were found in the liver 3 weeks after the onset of diabetes, compared to age matched control groups. Increased nitric oxide levels in diabetic vasculature and kidney, and its rapid reaction with reactive oxygen species, resulted in high peroxynitrite generation. This suggested the onset of processes characteristic to premature aging of the endothelium. According to the histopathological results, there were no signs of late complications in the tissues up to seven weeks after induction of diabetes. In conclusion, the authors' experimental evidences support the idea of a complex role for nitric oxide, reactive oxygen species and peroxynitrite in the development of early diabetic tissue injury before the evolution of late complications. This study showed for the first time a time-course dependence for changes in nitric oxide production in diabetic tissues compared to age-matched controls at an early stage of the disease. These results suggest that oxidative stress in increased at a very early stage of diabetes and, in particular, that high levels of nitric oxide and peroxynitrite could play a decisive role in the development of late complications in the diabetic vasculature and kidney

Histopathological Chromogranin A-Positivity Is Associated with Right-Sided Colorectal Cancers and Worse Prognosis

Background: Colorectal cancer (CRC) is known to be affected by paraneoplastic thrombocytosis and chromogranin A-positive neuroendocrine-cell differentiation (CgA+). Their combined effect has never been previously investigated. Methods: A prospective cohort pilot study of 42 CRC patients and 42 age- and sex-matched controls was carried out. Plasma interleukin-6, thrombopoietin, and serum chromogranin A and -B were measured; furthermore, tumor tissue was immunohistochemically stained for CgA+. Results: Twenty-seven and 15 patients were assigned to the chromogranin A-negative (CgA&minus;) and CgA+ groups, respectively. Within the CgA+ group, right-sided tumors were more frequent (18.5% vs. 53.3%), no stage I cancer was found, and patients of this group were in worse general condition. Compared to control subjects, chromogranin A level was higher in the CgA+ group (p = 0.0086), thrombopoietin (p = 0.0040) and chromogranin B (p = 0.0070) in the CgA&minus; group, while interleukin-6 was high in both tumor groups (p &le; 0.0090). Survival was significantly worse in the CgA+ group (hazard ratio: 5.73; p = 0.0378). Conclusions: Different thrombopoietin levels indicated distinct thrombocytosis types. Within the two CRC groups, serum levels of chromogranins changed in different directions suggesting two well-distinguishable pathophysiologies. Based on these observations we propose a new subtype of CRC, which can be characterized by chromogranin A-positive neuroendocrine-cell differentiation

Vaginal Progesterone Has No Diabetogenic Potential in Twin Pregnancies: A Retrospective Case-Control Study on 1686 Pregnancies

Background: In this study, we aimed to investigate the incidence of gestational diabetes mellitus (GDM) in women who carried twin pregnancies and received vaginal progesterone. Methods: In this retrospective cohort study, 203 out of 1686 women with twin pregnancies received natural progesterone (200 mg/day between gestational weeks 16 + 0 and 36 + 0) vaginally for &ge; 4 weeks. The control group consisted of 1483 women with twin pregnancies without progesterone administration. Pearson&rsquo;s Chi squared test, Fisher&rsquo;s exact test, and Student&rsquo;s t-test was used to compare differences between the control and the progesterone-treated groups. A multivariate binary logistic regression was performed to assess relative independent associations on the dependent outcome of GDM incidence. Results: Vaginal progesterone treatment in twin pregnancies had no significant influence on developing GDM (p = 0.662). Higher pre-pregnancy BMI (OR 1.1; p &lt; 0.001), GDM in previous pregnancy (OR 6.0; p &lt; 0.001), and smoking during pregnancy (OR 1.6; p = 0.014) posed an increased risk for developing GDM. Conclusion: In twin pregnancies, the use of vaginal progesterone for the prevention of recurrent preterm delivery was not associated with an increased risk of GDM